CN107412239B - Application of the glibenclamide in preparation protection induced lung injury drug - Google Patents
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Abstract
The present invention relates to pharmaceutical technology fields, provide application of the glibenclamide or derivatives thereof in preparation protection induced lung injury drug.Further, it the present invention also provides a kind of pharmaceutical composition for protecting induced lung injury, is made of glibenclamide or derivatives thereof and pharmaceutically acceptable auxiliary material.By mouse experiment in vivo, the extent of the destruction of blood vessel endothelium caused by the substantially reduced irradiation of glibenclamide energy, thus the case where inhibiting red blood cell exudation to increase, alleviate pulmonary hemorrhage after irradiating；It is tested by cell in vitro, glibenclamide can reduce cell according to rear apoptosis rate, improve Proliferation Ability situation.Illustrate that mouse induced lung injury can be mitigated with glibenclamide according to preceding, protect blood vessel endothelium, reduces vascular endothelial cell to the sensibility of radiation, protect induced lung injury to provide new foundation for glibenclamide or derivatives thereof.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to glibenclamide or derivatives thereof is in preparation protection lung radiation injury damage
Application in vulnerary object, and the pharmaceutical composition containing glibenclamide or derivatives thereof.
Background technique
Extensive use with nuclear radiation in fields such as industry, medical treatment, military affairs, employee exposed to radiation and the public are shone several
Rate greatly increases, the concern of radiation injury and protection more by educational circles and the public.In emergency cases such as nuclear war, nuclear accident
Under, related personnel, which is exposed under high-dose irradiation, can occur acute and chronic radiation sickness, wherein induced lung injury (Radiation-
Induced lung injury, RILI) it is of increasing concern because of its incidence height, difficult prevention, refractory treatment.
In addition, induced lung injury is also the common complication of breast tumor radiotherapy, when breast tumor radiotherapy, has
29.3% patient occurs with radioactive damage, therefore, the drug or method of effectively preventing induced lung injury is found, in army
Highly important meaning and application prospect are all had in thing medical domain and tumor radiotherapy.
The mechanism of induced lung injury is main are as follows: the intracorporal hydrone of ionization activation equipment of high-energy ray, into
And a large amount of free radical and active oxygen (ROS) are generated, the lung tissues parenchyma such as alveolar epithelial cells, vascular endothelial cell is made
At damage, the generation of induced lung injury is eventually led to (referring to document: Zhang Y, Zhang X, Rabbani ZN, Jackson
IL,Vujaskovic Z.Oxidative stress mediates radiation lung injury by inducing
apoptosis.Int J Radiat Oncol Biol Phys.2012；83(2):740-8).
It is mainly at present active oxygen (ROS) scavenger (such as W2721), Yi Jikang for the therapeutic agent of induced lung injury
Scorching drug (such as hormone).But often secondary toxic action is larger for these drugs, and lacks specificity, and it is extensive in clinic to limit it
Using.Therefore, it finds that a kind of new, effective, toxic side effect is small, high specificity therapeutic agent, is current radioecology
With the key points and difficulties of radiation medicine research.
Glibenclamide (Glibenclamide, CAS accession number 10238-21-8) is a kind of medicine for treating diabetes of classics
Object, action target spot are ATP sensitivity potassium-channel (ATP sensitive potassium channel, KATPChannel).It crosses
Go to be concentrated mainly on the research of glibenclamide in the effect that it promotes insulin secretion (referring to document: Riefflin A,
Ayyagari U,Manley SE,Holman RR,Levy JC.The effect of glibenclamide on insulin
secretion at normal glucose concentrations.Diabetologia.2015；58(1):43-9.).Closely
It is many study found that glibenclamide can be by targeting K over yearATPIntracellular ROS content is reduced in turn (referring to document: Li in channel
DL,Ma ZY,Fu ZJ,et al.Glibenclamide decreases ATP-induced intracellular
calcium transient elevation via inhibiting reactive oxygen species and
mitochondrial activity in macrophages.PLoS One.2014；9(2):e89083.).
Preventive and therapeutic effect there has been no document report glibenclamide in induced lung injury at present.
Summary of the invention
The purpose of the present invention is to provide a kind of new medical usages of glibenclamide or derivatives thereof, and arrange containing lattice
The pharmaceutical composition of this urea or derivatives thereof.
The first aspect of the present invention is that providing glibenclamide or derivatives thereof protects induced lung injury drug in preparation
In application, the protection induced lung injury drug be mitigate irradiation after empsyxis, reduce cell according to rear apoptosis rate or mitigate shine
Penetrate the drug of cell proliferation inhibition.Wherein, the drug of empsyxis is to reduce lung tissue blood vessel endothelium to break after the mitigation irradiation
Bad drug.
Further, protection induced lung injury drug is the drug for reducing reactive oxygen species (ROS) content.By preceding described
It is found that ROS increase be induced lung injury occur key link, reduce intracellular ROS content facilitate lung radiation injury damage
The protection of wound.
Glibenclamide derivative in the present invention refers to play the glibenclamide compound of pharmacological action, as lattice arrange
This urea difluoro derivatives etc..
In order to verify glibenclamide for the protection effect of induced lung injury, the present invention by mouse experiment in vivo and
It is anti-to the radiation of mouse lung tissue and vascular endothelial cell HUVEC that two aspects of cytological experiment in vitro demonstrate glibenclamide
Shield effect.
For experimental selection C57/BL6 in Mice Body, the male mice of 7 week old is tested, and irradiation gives small for first 1 hour
Glibenclamide (10mg/kg) is injected intraperitoneally in mouse.Protect the radiation modality of mouse for the local irradiation of single chest, dosage 30Gy,
Dosage rate is 1Gy/min, and irradiation source uses 60Co gamma-rays；For cytological experiment in vitro, irradiate first 1 hour, 100 μ
The glibenclamide of mol/L handles vascular endothelial cell HUVEC, and the exposure dose that the HUVEC cell of protection is received is 8Gy, agent
Dose rate 1Gy/min, irradiation source are 60Co gamma-rays.
It is found through experiments that, mouse is according to mouse lung bleeding, red blood cell caused by the substantially reduced irradiation of the energy of administration in first 1 hour
Exudation increases, and protects pulmonary epithelial cells and pulmonary vascular endothelial cell, reduces its apoptosis；Vascular endothelial cell HUVEC is carried out
Experiment, irradiation can induce vascular endothelial cell and apoptosis occur, inhibits cell Proliferation, and gives glibenclamide before shining and handle 1 hour
Cell be can be reduced according to rear apoptosis rate, improve Proliferation Ability situation.Illustrate that mouse lung radiation injury can be mitigated with glibenclamide according to preceding
Blood vessel endothelium is protected in damage, reduces vascular endothelial cell to the sensibility of radiation.
Protection induced lung injury drug of the present invention is that glibenclamide or derivatives thereof is used as sole active composition
Pharmaceutical composition either comprising glibenclamide or derivatives thereof.
Any dosage form, such as its can be made with pharmaceutically common auxiliary material in drug of the present invention or pharmaceutical composition
It can be as decoction, powder, pill, vina, pastille, jelly, plaster, medicinal tea, herbal leaven, cake agent, distillate medicinal water, stylus, line agent, item
Agent, paste, sublimed preparation, microencapsulation, vein emulsion, Liposomal formulation, aerosol, precursor medicine preparation, injection are pressed in agent, nail agent, moxibustion
Agent, mixture, peroral ampule agent, tablet, capsule, pill, emulsion, ointment, rubber plaster, film, sponginum, ion are saturating
Enter agent or cutaneous permeable agent.
The second aspect of the present invention is to provide a kind of pharmaceutical composition for protecting induced lung injury, by glibenclamide or
Its derivative and pharmaceutically acceptable auxiliary material composition.
Glibenclamide of the invention or derivatives thereof is for preventing induced lung injury, especially suitable for nuclear war, core thing
Therefore employee exposed to radiation, breast tumor radiotherapy in the treatment patient etc. with induced lung injury.Glibenclamide of the invention or its
Derivative is used especially for prevention induced lung injury, i.e., delivers medicine to the crowd that may meet with induced lung injury in advance, is administered
Mode is not limited to take orally, inject.
The action and effect of invention
By mouse experiment in vivo, the extent of the destruction of blood vessel endothelium caused by the substantially reduced irradiation of glibenclamide energy, thus
The case where inhibiting red blood cell exudation to increase, alleviate pulmonary hemorrhage after irradiating；It is tested by cell in vitro, glibenclamide energy
It enough reduces cell and shines rear apoptosis rate, improve Proliferation Ability situation, illustrate that mouse lung radiation injury can be mitigated with glibenclamide according to preceding
Blood vessel endothelium is protected in damage, reduces vascular endothelial cell to the sensibility of radiation.Therefore, the present invention is glibenclamide or it spreads out
Biological protection induced lung injury provides new foundation.
Further, since glibenclamide is mature Remedies for diabetes, trade name has glibenclamide, Maninil, reaches peace
Peaceful etc., pharmacological action is clear, toxic side effect is small, and drug safety has obtained clinical approval, glibenclamide provided by the invention
New indication can comparatively fast realize clinical conversion, and the target spot " K of glibenclamideATPChannel " differential expression in different tissues
Larger (report at present main height be expressed in pancreas, liver, nerve, muscle, blood vessel endothelium etc. tissue), compared with other it is anti-put medicine and
Speech, specificity is stronger, reduces the toxic damages to its hetero-organization as far as possible, and therefore, glibenclamide is damaged in clinical radiation lung
There is great potential in the security application of wound.The present invention also provides new clinic to prevent and treat the damage of nuclear radiation bring
Drug.
Detailed description of the invention
Fig. 1 is influence result figure of the glibenclamide to empsyxis after mouse irradiation, wherein A is that glibenclamide mitigates mouse
The result figure of empsyxis after irradiation, B are the result figure of alveolar wall thickness measuring, for measuring lung tissue inner cell exudation degree.
Fig. 2 is glibenclamide to the influence result figure for irradiating caused mouse lung tissue Apoptosis.Wherein, A TUNEL
Method marks the result figure of apoptotic cell (positive is brown)；B is the quantitative statistics result figure of lung tissue apoptosis rate；C is lung
The quantitative statistics result figure of tissue blood vessel endothelial cell apoptosis rate.
Fig. 3 glibenclamide is wet to mouse lung tissue/the influence result figure of dry weight ratio.
Fig. 4 is the influence result figure of the apoptosis after glibenclamide shines Blood vessel endothelial cell line HUVEC.Wherein, A is
The result that AnnexinV/PI kit passes through flow cytomery；B is the quantitative system that glibenclamide influences apoptosis rate
Count result.
Fig. 5 is result figure of the glibenclamide to the inhibited proliferation of Blood vessel endothelial cell line HUVEC.
Specific embodiment
Below with reference to embodiment and attached drawing, the present invention will be described in detail.But the following example should not be regarded as to the present invention
The limitation of range.
Embodiment 1: glibenclamide can reduce injury of lungs, empsyxis after mouse irradiation
One, experimental method
Choose C57/BL6,7 week old male mice tested, by mouse be divided into non-irradiation group, glibenclamide group and
Three groups of control group.For non-irradiation group both without injection or without irradiation, glibenclamide group gives mouse abdomen in 1 hour before irradiation
Chamber injects glibenclamide (10mg/kg), and because glibenclamide is dissolved with dimethyl sulfoxide (DMSO), therefore control group mice gives abdomen
The DMSO solution of chamber injection same dose.
Glibenclamide group and control group mice irradiation use the local irradiation of single chest, dosage 30Gy, and dosage rate is
1Gy/min, irradiation source use 60Co gamma-rays.Lung is exposed to irradiation field when irradiation, and rest part uses lead block shielding, in order to avoid
Cause the damage at other positions.
Mouse lung tissue, which was won, respectively at the 1,3,5th day after irradiation carries out pathological examination.Pathological examination includes two aspects:
First is that HE is dyed, lung tissue structure and lesion situation are shown；(detailed step is referring to Roche (Roche) company second is that TUNEL method
Tunel kit specification) detection Apoptosis situation, usual apoptotic cell can be colored brown, by comparing brown cell
Proportion can reflect Apoptosis degree.In addition to pathological examination, we also measure mouse lung tissue it is wet/dry weight ratio, that is, survey
Lung tissue weight ratio after measuring the lung tissue and drying newly taken out, the exudation situation of lung tissue is indicated by the ratio, from
And injury of blood vessel degree is speculated indirectly.General injury of blood vessel is serious, and exudation increases, and wet/dry specific gravity of lung is high.
Two, experimental result
The above experimental result is shown by FIG. 1 to FIG. 3: (1) the 1st day control group after lung tissue section HE dyeing instruction irradiation
Occur a large amount of red blood cell exudations in the mouse lung tissue of (irradiation+DMSO group), blood vessel endothelium destroys, and irradiation+glibenclamide
For group compared with control group, red blood cell exudation is substantially reduced, and blood vessel endothelium, which destroys, reduces (Figure 1A)；The 1st day after irradiation, control group and lattice
The alveolar wall thickness for arranging this urea group is thickened, and is continuously increased as the irradiation time increases, but glibenclamide group
The thickened degree of alveolar wall thickness is far below the wall thickness thickened degree (Figure 1B) of control group.Therefore, glibenclamide alleviates mouse photograph
Rear empsyxis is penetrated, the exudation degree of lung tissue inner cell is also mitigated.
(2) TUNEL dyeing display irradiation causes Apoptosis to increase, and shows as brown cytosis, especially in the blood vessels
It is become apparent on chrotoplast.Glibenclamide group is compared with solvent control group, hence it is evident that reduces positive cell ratio (Fig. 2).
(3) lung tissue it is wet/dry weight ratio the results show that irradiation cause it is wet/dry weight than increase, and glibenclamide can mitigate it is wet/
Dry weight ratio illustrates that irradiation causes angiolysis, and lung's exudation increases, and glibenclamide alleviates the exudation of lung, protects lung
Blood vessel (Fig. 3).
Embodiment 2: glibenclamide mitigates the apoptosis after Blood vessel endothelial cell line HUVEC shines
One, experimental method:
In order to verify influence of the glibenclamide to Apoptosis after irradiation, to the Blood vessel endothelial cell line HUVEC after irradiation
Carry out Apoptosis detection.
Apoptosis detection is using the bis- dyes of AnnexinV/PI (being purchased from Invitrogen company) flow cytometer detection method, principle
Be: Apoptosis is the process of a procedural starting, can be divided into early apoptosis, two processes of late apoptic.In early apoptosis
When, phosphatidylserine (PS) can be become turning up from the state originally on the inside of cellular phospholipid film, at this time Annexin V can with it is outer
The PS turned over is combined, and a detection as early apoptosis indicates.Late apoptosis stage, permeability of cell membrane increase cell, this
When propidium iodide (Propidium Iodide, PI) as a kind of nucleic acid dye then can enter cell interior in conjunction with nucleic acid, carefully
Karyon is dyed to red.Fluorescein on Annexin V label, with PI conjunctive use can by the analysis of flow cytometer come
Identify Level of Apoptosis (including early apoptosis and late apoptic).
Glibenclamide (100 μM) is given to HUVEC (being purchased from school of life and health sciences) cell Yu Zhaoqian or DMSO processing 1 is small
When, then cell is irradiated, dosage 8Gy, dosage rate 1Gy/min.Vitellophag after 48 hours after irradiation carries out
Annexin V/PI dyeing, carries out flow cytometry.
Two, experimental result
As shown in figure 4, irradiation+glibenclamide group is substantially reduced compared with irradiation+DMSO group apoptosis rate, upper right and bottom right are shown as
Quadrant cell proportion reduces (Fig. 4 A).Apoptosis rate is that coordinate diagram right upper quadrant adds the sum of right lower quadrant cell proportion, is counted
Quantitative display, glibenclamide are substantially reduced cell according to rear apoptosis rate (Fig. 4 B).
Embodiment 3: glibenclamide mitigates irradiation to the inhibited proliferation of Blood vessel endothelial cell line HUVEC
One, experimental method:
The detection of ability of cell proliferation uses colony formation, principle are as follows: individual cells more than generation can shape in passage 6
At the cell mass of 50 cells or so, referred to as one clone can reflect ability of cell proliferation according to the number of clone and size.
Cell can have two kinds of forms of proliferative death and interphase death after receiving irradiation, therefore can be preferable with Clone forming Test
Reflect the proliferative capacity of cell.Concrete operation step are as follows: HUEVC cell is carried out bed board, is paved into list as far as possible by first 24 hours of irradiation
A cell, cell will form colony in proliferation, dyed and stain (blue) can be observed, and cell Proliferation is more vigorous, dye
Color dot number is more, and area is bigger, therefore can be used for evaluating the proliferative capacity of cell.Agent-feeding treatment is carried out after cell is adherent,
Give glibenclamide (100 μM) and DMSO is incubated for 1 hour, then irradiates.Exposure dose is respectively 8Gy and 12Gy, and dosage rate is
1Gy/min replaces culture medium according to after and continues to cultivate, carried out violet staining to cell at the 10th day, counts clone cell number
Mesh.
Two, experimental result
As shown in figure 5, comparing non-irradiation group (0Gy group), irradiation group cell (8Gy and 12Gy) clone formation number obviously subtracts
Few, clone's area is also smaller, and exposure dose dependence is presented.But glibenclamide is used, cell can be dramatically increased according to rear clone
Quantity illustrates that glibenclamide mitigates irradiation to the inhibiting effect of cell, promotes the proliferation according to rear cell.
Above-described embodiment explores injury of lungs and empsyxis after glibenclamide irradiates mouse, to blood by taking glibenclamide as an example
Endothelial cell line HUVEC is acted on according to rear apoptosis and to the mitigation of the inhibited proliferation of Blood vessel endothelial cell line HUVEC, but
The present invention is not limited to glibenclamide, the glibenclamide derivative that can play same pharmacological action also belongs to protection model of the invention
It encloses.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent defines.
Claims (5)
1. application of the glibenclamide in preparation protection induced lung injury drug.
2. application of the glibenclamide according to claim 1 in preparation protection induced lung injury drug, feature exist
In:
Wherein, the protection induced lung injury drug is empsyxis after mitigating irradiation, reduces cell according to rear apoptosis rate or mitigation
Irradiate the drug that cell proliferation inhibits.
3. application of the glibenclamide according to claim 2 in preparation protection induced lung injury drug, feature exist
In:
Wherein, the drug of empsyxis is the drug for reducing lung tissue blood vessel endothelium and destroying after the mitigation irradiation.
4. application of the glibenclamide according to claim 1 in preparation protection induced lung injury drug, feature exist
In:
Wherein, the protection induced lung injury drug is the drug for reducing intracellular reactive oxygen content.
5. application of the glibenclamide according to any one of claims 1 to 4 in preparation protection induced lung injury drug,
It is characterized by:
Wherein, it includes either Ge Lieben that the protection induced lung injury drug, which is using glibenclamide as sole active agent,
The pharmaceutical composition of urea.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660057A (en) * | 2004-12-29 | 2005-08-31 | 王召 | Solid dispersion and preoral combination of glibenclamide and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660057A (en) * | 2004-12-29 | 2005-08-31 | 王召 | Solid dispersion and preoral combination of glibenclamide and preparation method |
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